17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV ...dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.
The SCARE Guidelines were first published in 2016 and were last updated in 2018. They provide a structure for reporting surgical case reports and are used and endorsed by authors, journal editors and ...reviewers, in order to increase robustness and transparency in reporting surgical cases. They must be kept up to date in order to drive forwards reporting quality. As such, we have updated these guidelines via a DELPHI consensus exercise.
The updated guidelines were produced via a DELPHI consensus exercise. Members were invited from the previous DELPHI group, as well as editorial board members and peer reviewers of the International Journal of Surgery Case Reports. The expert group completed an online survey to indicate their agreement with proposed changes to the checklist items.
A total of 54 surgical experts agreed to participate and 53 (98%) completed the survey. The responses and suggested modifications were incorporated into the new 2020 guideline. There was a high degree of agreement amongst the SCARE Group, with all modified SCARE items receiving over 70% scores 7–9.
A DELPHI consensus exercise was completed and an updated and improved SCARE Checklist is now presented.
•This was a DELPHI consensus exercise to update the SCARE guidelines.•Of the invited surgical experts, 53 (98%) completed the survey. There was a high level of agreement within the SCARE Group.•The survey responses were incorporated as modifications, and an improved SCARE Checklist is now presented for use.
Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, ...two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.
Two algal feedstocks were prepared for direct comparison of their properties when converted to liquid hydrocarbon fuel. The first feedstock was prepared by growing an algal strain phototrophically ...using a biofilm based approach. The second feedstock employed the same algal strain but was stressed heterotrophically to significantly increase the lipid concentration. The algal feedstocks were converted to liquid hydrocarbon fuels. First, the whole algae (i.e. not defatted or lipid extracted) were converted to an intermediate biocrude using continuous hydrothermal liquefaction (HTL) at 350°C and 3000psig. The biocrudes were subsequently upgraded via catalytic hydrotreating (HT) at 400°C and 1500psig to remove oxygen and nitrogen as well as increase the hydrogen-to-carbon ratio. The yield and composition of the products from HTL and HT processing of the feedstocks are compared. A techno-economic analysis of the process for converting each feedstock to liquid fuels was also conducted. The capital and operating costs associated with converting the feedstocks to finished transportation fuels are reported. A fuel minimum selling price is presented as a function of the cost of the algal feedstock delivered to the HTL conversion plant. Heterotrophic stressing of the algae significantly increased the concentration of lipids compared to the phototrophically grown algae. The high lipid concentration resulted in a doubling of the yield to biocrude, and hence diesel fuel blendstock. Although heterotrophic stressing of algae is costly, results presented in this study suggest that the significant increase in fuel yield over phototrophic growth could more than offset increased feedstock production costs.
Farm-scale livelihood activities, greenhouse gas emissions (GHG) and carbon (C) sequestration in integrated smallholder crop-livestock system of Kenya. The numbers (1–5) represent farm components: ...(1) livestock, (2) manure management systems (MMS), (3) soil, (4) crops and (5) trees. The letters (a–e) are associated with fluxes of C and N: (a) fodder, crop residues and concentrates, (b) dung, urine and bedding materials, (c) inorganic fertiliser, manure and crop residues, (d) nitrogen uptake by crops, (e) the biomass harvested that can follow different pathways: livestock feed, compost heap or mulch.
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•Whole-farm GHG balances are needed to identify climate-smart options.•Coffee-dairy farms are mostly net sources of GHG at farm-scale.•Poor manure management can be a determining factor in the farm GHG balance.•Emissions are smoothed by zero grazing and larger soil and biomass C sequestration.•Improving GHG estimations requires developing EFs and site calibrations.
Climate-smart approaches have gained momentum in tropical, agricultural development. However, to date, few studies have examined whole-farm greenhouse gas (GHG) balances in smallholder crop-livestock systems. This study aimed to quantify GHG balances at farm-scale, identify GHG hotspots and assess mitigation options in coffee-dairy farms undergoing agricultural intensification in Central Kenya. In recent decades, decreasing farm size has forced the shift from extensive practices to zero-grazing systems and higher nitrogen (N) inputs. We hypothesised that different farm strategies and intensification levels determine the farm’s GHG balance. A farm typology was constructed through principal component analysis (PCA) and hierarchical clustering from 125 farms surveyed. Four farm types were identified ranging relatively from small to large farms, low to high livestock intensities, and low to high N input rates. Whole-farm GHG balances were estimated using an adapted version of the Cool Farm Tool (CFT). Farms were found to be net sources of GHG, averaging from 4.5tCO2eqha−1yr−1 in less intensive farms to 12.5tCO2eqha−1yr−1 in high intensive farms. Within the farm GHG hotspots identified, methane (CH4) from enteric fermentation processes accounted for 26–39% of total farm GHG emissions; nitrous oxide (N2O) and CH4 from manure management systems (MMS) for 26–38%; soil background and fertilizer induced N2O emissions for 24–29%; off-farm production of feeds and agrochemicals for 10–22%; and crop residue management (CRM) for the remaining 1–3%. Within the mitigation practices assessed, zero-grazing stalls already lowered the livestock maintenance energy requirements, reducing enteric fermentation emissions. Stall-feeding, however, brings the necessity-opportunity to manage the manure and our results showed that MMS can be a determining factor in the GHG balance. Increasing the frequency of manure collection from stalls in favour of solid storage systems can reduce N2O emissions by up to 75%. Furthermore, dry manure storage reduced the CH4 emissions of liquid slurry systems by more than 70%. Further benefits in terms of carbon (C) sequestration were identified along farm types from manure and crop residues applications in soils (with averages of −1.3 to −2.3tCO2eqha−1yr−1) and biomass growth in agroforestry systems (−1.2 to −2tCO2eqha−1yr−1). Together, soils and woody biomass offset 25–36% of farm emissions. We conclude that reduced farm size and increased livestock density lead to higher emissions per unit area, though this increase is smoothed by larger negative fluxes in soils (by higher C inputs) and woody biomass (by higher tree densities) until a steady state is reached. Average yield-scaled emissions, or product carbon footprints (CFs), resulted in 1.08kg CO2 eq kg coffee berry−1, 0.64kg CO2 eq kg maize−1 and 1.05kg CO2 eq kg milk−1 on average. CFs did not always differ between farm types and intensification levels, meaning that increases in productivity were not higher than increases in GHG fluxes from intensification. This may be due to: 1) increases in productivity are the result of more processes other than N inputs; and/or 2) emissions from N inputs are overestimated by EFs and GHG calculators. Smallholders may benefit in the near future from climate initiatives and further field characterisation, models calibration and monitoring are required to overcome critical levels of uncertainty and provide more accurate estimations of GHG balances at farm-scale.
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•Afrotropical Unionidae and Moncetia belong to Coelaturini.•Coelaturini diversified at a steady pace after colonization of Africa ~17 Ma.•Most diversification events occurred in ...sympatry and clades coincide with drainage basins.•Lake Tanganyika was colonized at least twice followed by intralacustrine diversification.•Biogeographic patterns in Coelaturini resemble those in other taxa, including fishes.
Invertebrates are exceptionally diverse, but many are in decline because of anthropogenic changes to their habitat. This situation is particularly problematic for taxa that are not well monitored or taxonomically poorly understood, because the lack of knowledge hampers conservation. Despite their important functional role in freshwater ecosystems, African bivalves of the family Unionidae remain poorly studied compared to their highly threatened relatives in Europe, the U.S.A. and Canada. To resolve relationships and to study diversification dynamics in space and time, we performed time-calibrated phylogenetic studies and biogeographical modeling on the unionids from the East African Rift System and surroundings, including representatives of all currently recognized Afrotropical genera except for Brazzaea (and Unio from southern Africa). Our analyses indicate that all sampled Afrotropical unionids belong to the tribe Coelaturini (subfamily Parreysiinae), as does the genus Moncetia from Lake Tanganyika, which is currently attributed to the family Iridinidae. Colonization of Africa from Eurasia by Parreysiinae occurred ~17 Ma ago, and the subsequent diversification of Coelaturini in Africa continued at a steady pace, although net diversification decreased over time as more niches and ecoregions became occupied. Clades in Coelaturini largely reflect drainage basins, with the oldest lineages and highest regional diversity occurring in Lake Tanganyika, followed by the Congo Basin watershed in general. The species assemblage of Lake Tanganyika reflects multiple independent events of colonization and intralacustrine diversification since the Late Miocene or Early Pliocene. The clades of other regions, including that containing the species from Lake Malawi, are comparatively young. Biogeographical analyses indicate that the colonization history was mainly driven by cladogenesis in sympatry, whereas few anagenetic events contributed to the modern distribution of Coelaturini. Ancestral range estimations demonstrate that Coelaturini originated in the Victoria and/or Tanganyika ecoregions, and that the Congo Basin played an essential role in the colonization of Africa by Coelaturini.
We used atomic force microscopy to measure the binding forces between Mucini (MUC1) peptide and a single-chain variable fragment (scFv) antibody selected from a scFv library screened against MUC1. ...This binding interaction is central to the design of molecules used for targeted delivery of radioimmunotherapeutic agents for prostate and breast cancer treatment. Our experiments separated the specific binding interaction from nonspecific interactions by tethering the antibody and MUC1 molecules to the atomic force microscope tip and sample surface with flexible polymer spacers. Rupture force magnitude and elastic characteristics of the spacers allowed identification of the rupture events corresponding to different numbers of interacting proteins. We used dynamic force spectroscopy to estimate the intermolecular potential widths and equivalent thermodynamic off rates for monovalent, bivalent, and trivalent interactions. Measured interaction potential parameters agree with the results of molecular docking simulation. Our results demonstrate that an increase of the interaction valency leads to a precipitous decline in the dissociation rate. Binding forces measured for monovalent and multivalent interactions match the predictions of a Markovian model for the strength of multiple uncorrelated bonds in a parallel configuration. Our approach is promising for comparison of the specific effects of molecular modifications as well as for determination of the best configuration of antibody-based multivalent targeting agents.
The five-year survival rate for women with ovarian cancer is very poor despite radical cytoreductive surgery and chemotherapy. Although most patients initially respond to platinum-based chemotherapy, ...the majority experience recurrence and ultimately develop chemoresistance, resulting in fatal outcomes. The current administration of cytotoxic compounds is hampered by dose-limiting severe adverse effects. There is an unmet clinical need for targeted drug delivery systems that transport chemotherapeutics selectively to tumor cells while minimizing off-target toxicity. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, and many are overexpressed in solid tumors, including ovarian cancer. This review summarizes the progress in engineered nanoparticle research for drug delivery for ovarian cancer and discusses the potential use of GPCRs as molecular entry points to deliver anti-cancer compounds into ovarian cancer cells. A newly emerging treatment paradigm could be the personalized design of nanomedicines on a case-by-case basis.
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